The present invention relates to a biologically active compound and compositions containing the same to improve symptoms of progressive, inflammatory and autoimmune arthritis. Despite the development of many arthritis drugs, arthritis remains to be a world wide serious disease due to an increasing aging population. Even though the death rate due to arthritis is low, the quality of life of an individual who suffers from this disease is sacrificed with lowered activity level and productivity.
Among many types of arthritis, the most significant one is rheumatoid arthritis. Rheumatoid arthritis is an autoimmune disease by the action of auto-reactive T lymphocytes. T lymphocyte causes rheumatoid anthritis via delated type hypersensitivity. It is not fully understood which antigen is recognized by T lymphocyte to cause this disease. Type II collagen is known to be the most probable one, but other possibilities cannot be excluded. Anti-histone autoantibody has been discovered even though it is not clear that this antibody is the cause of the disease.
Many drugs have been used to treat rheumatoid arthritis without a complete relief of the symptoms. Conventional drugs include non-steroidal anti-inflammatory drugs (NSAIDs, aspirin, ibuprofen), gold salt, penicilamine, and steroidal hormones. The steroidal hormone, which is most potent and effective, have side effects when taken for a long period. Recently, recombinant soluble receptor of tumor necrosis factor (TNF), that play a major role in the inflammation mechanism, is on trial for new treatments of rheumatoid arthritis. However, an improved formulation to treat symptoms of rheumatoid arthritis such as inflammation, edema, abnormal formation of new blood vessels, destruction of cartilage and bone erosion is required.
Collagen-induced arthritis (CIA) has been used as an animal model of the T-lymphoidal rheumatoid arthritis (Autoimmunity to Type II collagen: Experimental model of arthritis, J. Exp. Med. 146; 857-868 (1977)). When type II collagen was injected into mice, which are prone to develop arthritis, arthritis was induced within 2 weeks with symptoms such as formation of pannus, erosion of cartilage and bone. Like the rheumatoid arthritis, CIA also has the humoral and the cellular immune responses against collagen.
Histone is one of the major nuclear components in the cells and forms chromosomes with nucleic acids. Many different forms of histones (H1) were isolated from mammals other than humans. There are many reports regarding various physiological activities of histone H1.
The discovery and isolation of water-soluble histone H1 in bovine plasma and milk was reported in Biochem. J. Vol. 244, 675-682, 1987. Proc. Natl. Acad. Sci. U.S.A. vol. 82, 4871-4875, which reported that the major component of the homeostatic thymus hormone (HTH) is histone H1. Histone H1 circulates freely in the lymph and blood vessels and acts similar to hormones by having capabilities such as controlling the secretion of other hormones.
Ann. J. Med. Sci. vol. 250, 79-85, 1965 also reported that the HTH therapy could potentiate the immune system and resolve the immunological problems associated with thymectomy. WO 8503003A suggests using histone H1 fragment, which has the characteristics of thymus hormone, as an immunotherapy to prevent leukemia after thymectomy or radiotherapy of thymus. U.S. Pat. No. 5,182,257 disclosed histone H1, H2A, H2B, H3 and H4 as drugs for lymphoma or leukemia.
Chemical abstracts 74,85743 (1971) reported that, when taken together with T2 bacteriophage, histone H1 subunit could down-regulate the formation of antibodies against T2 bacteriophage. Chemical abstracts 73,96837 (1970) reported the use of histone H1 as an immunosuppressant for skin grafting.
Nature vol. 360, 33-39, 1992 reported that histone H1 can stabilize the flagellar microtubule structure of sea urchin. J. Biol. Chem vol. 259,15523-15531, 1984 reported that histone H1, acting with the microtubules isolated from murine brain, induces aggregation of tubulin which is similar to the ring structure of the microtubules.
No existing references, however, suggests using histone H1 as a drug to treat rheumatoid arthritis.